In many examples of natural products, an extended conjugated olefinic chain is present and important for biological effects. Many of the compounds within the arachidonic acid cascade (eicosanoids) are important modulators of inflammation. For example, leukotriene B4 has been detected in fluid from involved tissue in rheumatoid arthritis, gout, psoriasis and ulcerative colitis. (Bhattacherjee et al., Ann. N.Y. Acad. Sci., 524:307 (1984)). The absolute stereochemistry of the olefinic series is often an important feature of these compounds.
The retinoid members of the steroid/thyroid superfamily of receptors are responsive to compounds referred to as retinoids, which include retinoic acid, retinol (vitamin A), and a series of natural and synthetic derivatives which have been found to exert profound effects on development and differentiation in a wide variety of systems. Novel members of the steroid/thyroid superfamily of receptors have been identified which are not responsive to retinoic acid, called retinoid X receptors. 9-cis-retinoic acid has been demonstrated to have affinity for retinoid X receptors (Heyman et al., Cell, 68:397 (1992)), and other retinoids having 9-10 cis olefin geometry have been found to selectively activate retinoid X receptors.
Therefore, it would be advantageous to selectively prepare retinoid and retinoid-like compounds with the 9-10 olefin bond in a cis-configuration, and to prepare other polyene compounds having the desired stereochemistry.
The literature has examples of the preparation of 9-10 cis olefin retinoids, but none of which are specific in their construction of the 9-10 olefin bond. (See Robeson et al., J. Am. Chem. Soc., 77:4111 (1955); Matsui, et al., J. Vitaminol., 4:178 (1958); Pat. No. DE 1068719 (1958); Aurell, et al., Tetrahedron Lett., 31:5791 (1990). The stereoselective preparation of the 13-14 olefin bond has been reported. (Pattenden et al., J. Chem. Soc. (C), 1984 (1968); Mayer et al., Experientia, 34:1105 (1978). Other information helpful in the understanding and practice of the present invention can be found in: U.S. Pat. Nos. 3,006,939 (1961); DE 1050763 (1959); DE 1174769 (1964); DE 1068710 (1959).
The entire disclosures of the publications and references referred to above and hereafter in this specification are incorporated herein by reference.